Carboxyvinyl polymer-containing nanoparticle suspensions

ABSTRACT

The present invention generally relates to suspension compositions having a carboxyvinyl polymer such as a carbomer, a galactomannan such as guar, and a borate compound. A sparingly soluble particulate compound such as nepafenac is also included in the compositions. The sparingly soluble particulate compound has a small particle size to enhance bioavailability of the compound.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority under 35 U.S.C. §119 to U.S.Provisional Patent Application Ser. No. 61/266,368, filed Dec. 3, 2009,the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compositions for ophthalmic drugdelivery, and more specifically to nanoparticle suspensions comprising acarboxyvinyl polymer, a galactomannan, and borate.

BACKGROUND OF THE INVENTION

The topical administration of pharmaceuticals for ophthalmic indicationsis generally preferred for ease of use and patient compliance. Aqueoussolutions having physiologically-compatible pH and osmolality arerepresentative of delivery systems in this class. However, manypharmaceutical agents are relatively insoluble in aqueous vehicle andmust be delivered as a suspension. Often, such agents do not penetratecorneal tissue well. Suspensions can be diluted or flushed from the eyeby the tear film before the agent is able to enter the corneal tissue insufficient concentration.

Accordingly, various techniques have been used to improve the overallbioavailability of sparingly soluble pharmaceutical agents and increasethe concentration of such agents in targeted tissues. Increasing theviscosity of topically applied solutions to increase the retention timeof the solution on the cornea does not always lead to an increase inbioavailability, and may actually retard penetration of thepharmaceutical agent into the cornea. See, e.g., U.S. patent applicationSer. No. 11/429,736, filed May 8, 2006 and entitled “SuspensionFormulations of Nepafenac and other Ophthalmic Drugs for the TopicalTreatment of Ophthalmic Disorders”.

Ophthalmic compositions have been previously described that utilizegalactomannan-borate gelling systems. U.S. Pat. No. 6,403,609 toAsgharian, entitled “Ophthalmic compositions containing galactomannanpolymers and borate,” describes such systems and is herein incorporatedby reference in its entirety.

Ophthalmic compositions that enhance the corneal penetration ofsparingly soluble pharmaceutical agents such as nepafenac have beendisclosed in U.S. patent application Ser. No. 11/430,239 filed May 8,2006 entitled “Suspension Formulations of Nepafenac and other OphthalmicDrugs for Topical Treatment of Ophthalmic Disorders”. The '239application describes the use of poloxamer or meroxapol surfactant and aglycol tonicity-adjusting agent in compositions having good cornealpermeability of the active pharmaceutical. These compositions do notcomprise a carboxyvinyl polymer.

U.S. Pat. No. 5,188,826 discloses an ophthalmic gel suspension fortreating dry eye. The suspension compositions remain as a gel in the eyefor a prolonged time, and release water and one or more ophthalmicdemulcents or vasoconstrictors. The suspension compositions contain awater-insoluble, lightly cross-linked, carboxyl containing polymerhaving a particle size of not more than 50 μm in equivalent sphericaldiameter. The demulcent is preferably at least one of sodiumcarboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, dextran 70, gelatin, glycerin, polyethyleneglycol, polysorbate 80, propylene glycol, polyvinyl alcohol orpolyvinylpyrrolidone. Particularly preferred as the carboxyl-containingpolymer is CARBOPOL® 976. The suspension compositions do not contain aprescription drug.

U.S. Pat. No. 5,192,535 discloses suspension compositions of ophthalmicdrugs that have suitably low viscosities to permit easy administrationin drop form, but which rapidly gel in the eye to provide sustained drugrelease. The suspension compositions are formulated at a pH of fromabout 3 to about 6.5 and contain a water-insoluble, carboxyl-containingpolymer prepared by polymerizing one or more carboxyl-containingmonoethylenically unsaturated monomers and less than about 5% by weightof a cross-linking agent. CARBOPOL® 976 and polycarbophil are identifiedas examples of suitable carboxyl-containing polymers. These formulationsgel in the eye due to the thermogelling properties of the polymers. Ionexchange resins may be included as one type of adjuvant in thesuspension compositions. Demulcents are identified as one of many typesof medicaments suitable for use in the suspension compositions.

BRIEF SUMMARY OF THE INVENTION

The present invention generally relates to topical aqueous ophthalmicnanoparticle suspensions comprising a sparingly soluble particulatecompound (e.g., pharmaceutical agents), carboxyvinyl polymer,galactomannan, and borate. A preferred composition of the presentinvention is a nepafenac suspension comprising a carboxyvinyl polymer ofacrylic acid cross-linked with allyl sucrose or allylpentaerythritol,guar, and boric acid.

Compositions of the present invention are physiologically compatible andprovide good bioavailability for sparingly soluble particulate compoundssuch as nepafenac, even at infrequent dosing intervals such as once ortwice daily. Maintaining the viscosity of carboxyvinyl polymer solutionsis generally quite difficult, as the viscosity imparted by carboxyvinylpolymer is very sensitive to salt concentration; accordingly suchsolutions often do not comprise sodium chloride. However, as the tearfilm comprises a relatively high concentration of sodium chloride, theviscosity of a carboxyvinyl polymer solution typically decreases oncetopically applied to the eye. The present inventors have found that theviscosity of carboxyvinyl polymer solutions can be maintained if thesolution also contains a galactomannan and borate. The carboxyvinylpolymer, galactomannan, and borate compositions of the present inventionhave a stable viscosity when applied to the eye, and provide for goodbioavailability of sparingly soluble particulate compounds. The presentinventors have also found that a reduced particle size of 50 to 700 nmimproves the bioavailability of such compounds in target tissues usingtopical ophthalmic suspensions.

The foregoing brief summary broadly describes the features and technicaladvantages of certain embodiments of the present invention. Additionalfeatures and technical advantages will be described in the detaileddescription of the invention that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete understanding of the present invention and theadvantages thereof may be acquired by referring to the followingdescription, taken in conjunction with the figures of the accompanyingdrawing in which like reference numbers indicate like features andwherein;

FIG. 1 is a graph showing the concentration of amfenac (a nepafenacmetabolite) in the rabbit iris ciliary body following administration oftopical nepafenac formulations;

FIGS. 2 a and 2 b are graphs showing the concentration of amfenac inrabbit aqueous humor and iris ciliary body at various time pointsfollowing administration of topical nepafenac formulations; and

FIGS. 3 a and 3 b are bar charts showing the area under the curve ofconcentration vs. time plots of nepafenac and amfenac in rabbit aqueoushumor and iris ciliary body after application of topical nepafenacformulations.

DETAILED DESCRIPTION OF THE INVENTION

Compositions of the present invention comprise a carboxyvinyl polymer.The carboxyvinyl polymers have an approximate molecular weight of fromabout 50,000 to about 6 million daltons. The polymers are characterizedas having carboxylic acid functional groups. Preferred carboxyvinylpolymers include water-soluble and water-swellable carbomers. Many suchcarbomers are available under the trade name CARBOPOL® from LubrizolCorporation. Carbomer polymers are crosslinked, acrylic acid-basedpolymers. They are cross-linked with allyl sucrose orallylpentaerythritol. Carbomer copolymers are polymers of acrylic acid,modified by C₁₀₋₃₀ alkyl acrylates, and crosslinked withallylpentaerythritol. A preferred carbomer for use in the compositionsof the present invention is a polymer of acrylic acid cross-linked withallyl sucrose or allylpentaerythritol, which is commercially availableas CARBOPOL® 974P. The amount of carboxyvinyl polymer present in thesuspension compositions of the present invention ranges from about 0.1to 1.0 w/v %, preferably 0.1 to 0.5 w/v %, and most preferably 0.4 w/v%.

In addition to a carboxyvinyl polymer, the compositions of the presentinvention utilize a galactomannan-borate system in aqueous solution. Aborate anion will condense onto the cis-diol groups of a galactomannanmolecule, and may cross-link with a second galactomannan molecule.Cross-linking of borate and galactomannan is influenced by factors suchas pH, among others, and such cross-linking in turn influences theviscosity of the solution.

The types of galactomannans that may be used in the present inventionare typically derived from guar gum, locust bean gum and tara gum. Asused herein, the term “galactomannan” refers to polysaccharides derivedfrom the above natural gums or similar natural or synthetic gumscontaining mannose or galactose moieties, or both groups, as the mainstructural components. Preferred galactomannans of the present inventionare made up of linear chains of (1-4)-β-D-mannopyranosyl units withα-D-galactopyranosyl units attached by (1-6) linkages.

With the preferred galactomannans, the ratio of D-galactose to D-mannosevaries, but generally will be from about 1:2 to 1:4. Galactomannanshaving a D-galactose:D-mannose ratio of about 1:2 are most preferred.Additionally, other chemically modified variations of thepolysaccharides are also included in the “galactomannan” definition. Forexample, hydroxyethyl, hydroxypropyl and carboxymethylhydroxypropylsubstitutions may be made to the galactomannans of the presentinvention. Non-ionic variations to the galactomannans, such as thosecontaining alkoxy and alkyl (C1-C6) groups are particularly preferredwhen a soft gel is desired (e.g., hydroxylpropyl substitutions).Substitutions in the non-cis hydroxyl positions are most preferred. Anexample of non-ionic substitution of a galactomannan of the presentinvention is hydroxypropyl guar, with a molar substitution of about 0.4.Anionic substitutions may also be made to the galactomannans. Anionicsubstitution is particularly preferred when strongly responsive gels aredesired. A galactomannan is typically present in a formulation of thepresent invention at a concentration of about 0.01 to about 10 w/v %,preferably at about 0.1 w/v % to about 2.0 w/v %, and most preferably atabout 0.1 to about 0.4 w/v %. Preferred galactomannans of the presentinvention are guar, native guar, and hydroxypropyl guar. In a preferredembodiment of the present invention, native guar is present at aconcentration of about 0.2 w/v %. Native guar is particularly preferred,for example, USP or general grade native guar powder obtained from TICGums, Inc. A process for producing a particularly preferred native guaris disclosed in co-pending U.S. patent application Ser. No. 12/701,339,entitled “Process for Purifying Guar” filed Feb. 5, 2010.

The borate compounds which may be used in the compositions of thepresent invention include, but are not limited to, boric acid and otherpharmaceutically acceptable salts such as sodium borate (borax) andpotassium borate. Borate is typically present at a concentration of 0.2to 2.0 w/v %, more preferably at a concentration of 0.4 to 0.6 w/v %,and most preferably at about 0.5 w/v %. As used herein, the term“borate” refers to all pharmaceutically suitable forms of borates,including but not limited to boric acid, and alkali metal borates suchas sodium borate and potassium borate. Boric acid is the preferredborate used with embodiments of the present invention.

Certain aqueous compositions of the present invention contain apharmaceutically effective amount of nepafenac or other sparinglysoluble particulate compound. As used herein, “sparingly soluble inwater” or “sparingly-soluble particulate compound” means a compound orpharmaceutical agent that has a solubility limit in water at 25° C. inthe range of 0.001 to 0.1 w/v %. Nepafenac is a known nonsteroidalanti-inflammatory compound, and can be made by known methods. See, forexample, U.S. Pat. Nos. 5,475,034 and 4,313,949, the entire contents ofwhich are incorporated by reference. Nepafenac is also known as2-amino-3-benzoylphenylacetic acid. The topical use of nepafenac andother amide and ester derivatives of 3-benzoylphenylacetic acid to treatophthalmic inflammation and pain is disclosed in U.S. Pat. No.5,475,034. The nepafenac compositions of the present invention willgenerally contain 0.1 to 1.0 w/v %, preferably 0.25 to 0.35 w/v %, andmost preferably about 0.3 w/v % nepafenac.

The present inventors have found that decreasing the particle size ofnepafenac in certain compositions of the present invention enhances thebioavailability of nepafenac. Preferred compositions accordingly have anaverage particle size of 50 to to 700 nm, a more preferred averageparticle size of 100 to 600 nm, and a most preferred average particlesize of 400 nm. Methods to produce nanometer and submicron particles ofdrugs are known, including, but not limited to, milling, high pressurehomogenization, or small crystal formation from solutions.

Other sparingly soluble particulate compounds that may be used inembodiments of the present invention include, but are not limited to,nonsteroidal anti-inflammatory compounds, carbonic anhydrase inhibitors,antifungal agents, phosphodiesterase IV inhibitors, receptor tyrosinekinase inhibitors, rho kinase inhibitors, brakykinin agonists, CNPagonists, H1/syk kinase inhibitors, VEGF inhibitors, antibodies andfragments thereof, TNF-α inhibitors, halogenated compounds such ashalogenated amino acids, and steroids.

Compositions of the present invention are ophthalmically suitable forapplication to a subject's eyes. These drops may be delivered from asingle dose ampoule which may preferably be sterile and thus renderbacteriostatic components of the formulation unnecessary. Alternatively,the drops may be delivered from a multi-dose bottle which may preferablycomprise a device which extracts any preservative from the formulationas it is delivered, such devices being known in the art.

The compositions of the present invention may optionally comprise one ormore additional excipients and/or one or more additional activeingredients (e.g., pharmaceutical agents). Excipients commonly used inpharmaceutical compositions include, but are not limited to, demulcents,tonicity agents, preservatives, preservative aids, chelating agents,buffering agents, and surfactants. Other excipients comprisesolubilizing agents, viscosity-adjusting agents, stabilizing agents,comfort-enhancing agents, polymers, emollients, pH-adjusting agentsand/or lubricants.

The compositions of the present invention optionally contain metalchloride salts (such as sodium chloride) or non-ionic tonicity adjustingagents (such as propylene glycol or hydroxyl compounds) as additionaltonicity-adjusting agents. Suitable buffering agents include, but arenot limited to, phosphates, acetates and the like, and amino alcoholssuch as 2-amino-2-methyl-1-propanol (AMP). In a preferred composition, ametal chloride such as sodium chloride is present at a concentration of0.15 to 0.5 w/v %, and most preferably at 0.4 w/v %.

The compositions set forth herein may comprise one or morepreservatives. Many ophthalmically acceptable preservatives are knownand include, but are not limited to, benzalkonium halides andpolyquarternium-1. Most preferred preservatives are benzalkoniumchloride (“BAC”) and polyquarternium-1. In the case of benzalkoniumchloride, the preservative is preferably present in an amount from 0.001to 0.02%, and most preferably 0.005%.

The compositions of the present invention are preferably isotonic, orslightly hypotonic in order to combat any hypertonicity of tears causedby evaporation and/or disease. This may require a tonicity agent tobring the osmolality of the formulation to a level at or near 250-350milliosmoles per kilogram (mOsm/kg). The compositions of the presentinvention generally have an osmolality in the range of 250 to 350mOsm/kg. The ophthalmic compositions will generally be formulated assterile aqueous solutions. The term “aqueous” typically denotes anaqueous formulation wherein the formulation is >50%, morepreferably >75% and in particular >90% by weight water.

The aqueous compositions of the present invention optionally compriseone or more buffering agents, such as phosphate buffers (e.g., disodiumphosphate and monosodium phosphate) and citrate buffers. The bufferingagent is chosen based upon the target pH for the composition, whichgenerally ranges from pH 5.0 to 8.5. The target pH for the compositiondepends upon the chosen ophthalmic drug. In the case of nepafenac, thedesired pH is preferably 5.0 to 7.2, and most preferably 6.0.Ophthalmically acceptable pH adjusting agents are known and include, butare not limited to, hydrochloric acid (HCl) and sodium hydroxide (NaOH).In one particularly preferred embodiment the pH of the composition is5.8 to 6.8.

Nonionic milling agents such as tyloxapol, polysorbate 80, and sodiumcarboxylmethylcellulose may be included in certain embodiments of thepresent invention. If present, such milling agents have a concentrationof 0.005 to 0.1 w/v % in the compositions of the present invention.

Suitable chelating agents include edetate disodium; edetate trisodium;edetate tetrasodium; and diethyleneamine pentaacetate. Most preferred isedetate disodium. If included, the chelating agent will typically bepresent in an amount from 0.001 to 0.1 w/v %. In the case of edetatedisodium, the chelating agent is preferably present at a concentrationof 0.01%.

The compositions of the present invention can be used to treat manyophthalmic disorders. These disorders include, but are not limited to,ocular surface and retinal disorders, glaucoma, dry eye, ocular surfacepain, uveitis, scleritis, episcleritis, keratitis, surgically-inducedinflammation, endophthalmitis, iritis, atrophic macular degeneration,retinitis pigmentosa, iatrogenic retinopathy, retinal tears and holes,macular edema (e.g., cystoid macular edema), diabetic macular edema,diabetic retinopathy, sickle cell retinopathy, retinal vein and arteryocclusion, optic neuropathy, exudative macular degeneration, neovascularglaucoma, corneal neovascularization, cyclitis, sickle cell retinopathy,and pterygium.

In preferred embodiments, a composition of the present invention isadministered once a day. The enhanced bioavailability of certaincompositions of the present invention allows once-a-day dosing fornepafenac-containing compositions. This dosing regimen improves patientcompliance and the odds of successful treatment. However, thecompositions may also be formulated for administration at any frequencyof administration, including once a week, once every 5 days, once every3 days, once every 2 days, twice a day, three times a day, four times aday, five times a day, six times a day, eight times a day, every hour,or greater frequency. Such dosing frequency is also maintained for avarying duration of time depending on the therapeutic regimen. Theduration of a particular therapeutic regimen may vary from one-timedosing to a regimen that extends for months or years. One of ordinaryskill in the art would be familiar with determining a therapeuticregimen for a specific indication.

Certain aspects of the present invention possess numerous advantages.Gelling compositions form clear and colorless gels and do not interferewith vision. The gels are activated by minor pH changes when applied tothe eye. Furthermore, guar and carbomer polymers do not have a cloudpoint when autoclaved, and accordingly provide for easy sterilization.These polymers are also compatible with many commonly used excipients.

The following examples are presented to further illustrate selectedembodiments of the present invention.

Example 1

Ingredient Amount (w/v %) Nepafenac 0.3 Sodium Carboxymethylcellulose0.06 Carbopol 974p 0.4 Native Guar Gum 0.2 Boric Acid 0.5 SodiumChloride 0.4 Propylene Glycol 0.5 Benzalkonium Chloride 0.005 DisodiumEDTA (Edetate Disodium) 0.01 Sodium Hydroxide/Hydrochloric Acid q.s. pH7.0 Purified Water q.s. 100%

Example 2

Ingredient Amount (w/v %) Rimexolone 0.01-3.0 Tyloxapol 0.01-0.1Carbopol 974  0.2-0.6 Guar Gum   01-0.3 Boric acid 0.25-1.0 Sodiumchloride  0.2-0.5 Propylene glycol  0.5-1.5 Disodium EDTA    0-0.01Benzalkonium chloride 0.003-0.01 Hydrochloric acid q.s. to pH 7.0 Sodiumhydroxide q.s. to pH 7.0 Purified Water q.s. to 100%

Example 3

FIG. 1 is a graph showing the concentration of amfenac (a nepafenacmetabolite) in the rabbit iris ciliary body (ICB) following a dose of acommercial 0.1 w/v % suspension of nepafenac (NEVANAC®) compared toformulations of 0.3 w/v % nepafenac in carbopol (FID114971) andcarbopol/guar/borate (FID114949). The graph demonstrates that thecarbopol/guar/borate formulation provides better bioavailability than asimilar formulation comprising carbopol only. The NEVANAC formulationhad lower amounts of amfenac in the ICB compared to thecarbopol/guar/borate formulation.

Example 4

The distribution of nepafenac and its metabolite, amfenac, was studiedin New Zealand white rabbits. Rabbits were dosed bilaterally,sacrificed, and aqueous humor (AH) and iris ciliary body (ICB) tissuewere analyzed using LC/MS/MS. The data for each time point shown inFIGS. 2 a and 2 b is the average of concentrations measured from 6rabbit eyes. Animals dosed TID received three doses 8 hours apart for 4days, with a single dose in the morning of day 5. Animals dosed QDreceived one dose for 5 days.

FIGS. 2 a and 2 b are graphs showing the concentration of amfenac inrabbit aqueous humor and iris ciliary body at various time pointsfollowing administration of nepafenac formulations. FIGS. 3 a and 3 bare bar charts showing the area under the curve of concentration vs.time plots of nepafenac and amfenac in rabbit aqueous humor and irisciliary body after application of topical nepafenac formulations. Thefigures indicate that the carbopol/guar nepafenac formulations testedconsistently produced higher bioavailability than currently marketednepafenac formulations and formulations having carbopol only. Upontopical ocular administration, the carbopol/guar nepafenac formulation(FID 114949) showed higher bioavailability than the carbopol onlyformulation (FID 104045). When the nepafenac particle size was reducedto approximately 400 nm, the nanoparticle carbopol/guar formulation (FID115535) showed increased bioavailability to formulations having largerparticle size. All carbopol/guar formulations produced higher aqueoushumor and iris ciliary body amfenac concentrations at all time points,as shown in FIGS. 2 a and 2 b.

The carbopol/guar nanosuspension of nepafenac was made in the followingmanner. In a 2000 mL glass vessel, was taken 200 g of 2% CARBOPOL® 974Pstock solution. To it were sequentially added 5 g boric acid, 4 g sodiumchloride and about 200 g of purified water. Stirred well to dissolve andpH was adjusted to 7.0. To this was added 400 g of 0.5% stock solutionof guar and mixed thoroughly. To this solution was added 5 g propyleneglycol, 5 g of 1% benzalkonium chloride stock solution and 10 g of 1%disodium. EDTA stock solution. The solution pH was checked and adjustedto 950 g by the addition of purified water. This solution was autoclavedat 121° C. for 35 minutes. Upon cooling, 60 g of 5% stock slurry ofnepafenac in CMC solution was added. The resulting solution was stirredwell and q.s. to 100% of batch size by purified water.

The nepafenac slurry was made in the following manner. In a 1000 mLglass vessel, 10 g sodium carboxymethyl cellulose (CMC) 7LF PH wasallowed to hydrate for 2 hours, and then autoclaved for 35 minutes at121° C. A 3-5% slurry of nepafenac was aseptically prepared in the aboveCMC solution. The suspension was homogenized using a hand heldhomogenizer for 10 min. at 5000-10000 RPM. The slurry was thenaseptically milled with a Netszch Minicer High Energy Mill (HEM) using140 mL of 0.2 mm Zr beads in a clean room for 30 min at 3000 RPM toachieve the targeted particle size. The resulting slurry was checked forparticle size.

The present invention and its embodiments have been described in detail.However, the scope of the present invention is not intended to belimited to the particular embodiments of any process, manufacture,composition of matter, compounds, means, methods, and/or steps describedin the specification. Various modifications, substitutions, andvariations can be made to the disclosed material without departing fromthe spirit and/or essential characteristics of the present invention.Thus, the following claims are intended to encompass within their scopemodifications, substitutions, and variations to processes, manufactures,compositions of matter, compounds, means, methods, and/or stepsdisclosed herein. All patents and publications mentioned in thespecification are herein incorporated by reference to the same extent asif each individual publication was specifically and individuallyindicated to be incorporated by reference.

1. A topically administrable aqueous ophthalmic suspension compositioncomprising: a carboxyvinyl polymer at a concentration of 0.1 to 0.5 w/v%; a galactomannan at a concentration of 0.1 to 0.4 w/v %; borate at aconcentration of 0.4 to 2.0 w/v %; and a sparingly soluble particulatecompound, said compound having a solubility in water at 25° C. of 0.001to 0.1 w/v % and a particle size of 50 to 700 nm.
 2. A compositionaccording to claim 1, further comprising a pH-adjusting agent in anamount sufficient to cause the composition to have a pH of 5.0 to 7.2.3. A composition according to claim 1, further comprising atonicity-adjusting agent in an amount sufficient to cause thecomposition to have an osmolality of 250 to 350 mOsm/kg.
 4. Acomposition according to claim 1 wherein said sparingly solubleparticulate compound is nepafenac at a concentration of 0.1 to 1.0 w/v%.
 5. A composition according to claim 1 wherein said carboxyvinylpolymer is carbomer at a concentration of 0.4 w/v %.
 6. A compositionaccording to claim 1 further comprising a milling agent at aconcentration of 0.005 to 0.1 w/v %.
 7. A composition according to claim6 wherein said milling agent is a surfactant or polymer.
 8. Acomposition according to claim 7 wherein said milling agent is sodiumcarboxylmethylcellulose.
 9. A composition according to claim 1 furthercomprising a metal chloride salt tonicity-adjusting agent.
 10. Acomposition according to claim 9 wherein said metal chloride salt issodium chloride at a concentration of 0.4 w/v %.
 11. A compositionaccording to claim 1 further comprising a non-ionic hydroxyl compound asa tonicity-adjusting agent.
 12. A composition according to claim 1further comprising both a preservative and a chelating agent.
 13. Acomposition according to claim 12 wherein the preservative isbenzalkonium chloride at a concentration of 0.005 w/v % and thechelating agent is edetate disodium at a concentration of 0.01 w/v %.14. A composition according to claim 1 wherein said carboxyvinyl polymeris carbomer, said galactomannan is guar, said borate is boric acid, andsaid sparingly soluble particulate compound is nepafenac at aconcentration of 0.1 to 1.0 w/v %.
 15. A composition according to claim14 comprising 0.4 w/v % carbomer, 0.2 w/v % guar, 0.5 w/v % boric acid,and 0.3 w/v % nepafenac.
 16. A composition according to claim 15 whereinsaid nepafenac has an average particle size of 400 nm.
 17. A method oftreating ophthalmic disorders in a patient comprising topicallyadministering to the patient a composition according to claim
 1. 18. Amethod according to claim 17 wherein said ophthalmic disorder isselected from the group consisting of: ocular surface and retinaldisorders, glaucoma, dry eye, ocular surface pain, uveitis, scleritis,episcleritis, keratitis, surgically-induced inflammation,endophthalmitis, iritis, atrophic macular degeneration, retinitispigmentosa, iatrogenic retinopathy, retinal tears and holes, macularedema, cystoid macular edema, diabetic macular edema, diabeticretinopathy, sickle cell retinopathy, retinal vein and artery occlusion,optic neuropathy, exudative macular degeneration, neovascular glaucoma,corneal neovascularization, cyclitis, sickle cell retinopathy, andpterygium.
 19. A topically administrable ophthalmic suspensioncomposition consisting essentially of a) 0.3 w/v % nepafenac having aparticle size of 50 to 700 nm; b) 0.4 w/v % carbomer; c) 0.2 w/v % guar;d) 0.5 w/v % boric acid; e) 0.06 w/v % sodium carboxylmethylcellulose;f) 0.4 w/v % sodium chloride; g) 0.5 w/v % propylene glycol; h) apH-adjusting agent in an amount sufficient to cause the composition tohave a pH of 7.0; i) 0.005% (w/v) benzalkonium chloride; j) 0.01%edetate disodium; and k) purified water.
 20. A method for maintainingthe viscosity of a topical ophthalmic composition comprising 0.1 to 0.5w/v % carbomer when said composition is topically applied to the eye,the method comprising: adding galactomannan sufficient to provide aconcentration of 0.1 w/v % to 0.4 w/v % galactomannan in saidcomposition, and borate sufficient to provide a concentration of 0.4 w/v% to 0.6 w/v % in said composition.
 21. A method according to claim 20,wherein said composition has a pH of 5.0 to 7.2.
 22. A method accordingto claim 20, wherein said composition further comprises a sparinglysoluble particulate compound.
 23. A method according to claim 22,wherein said sparingly soluble particulate compound is nepafenac at aconcentration of 0.3 w/v %.